Socratech L.L.C. is a start-up company within the University of Rochester founded in July 2000 with a focus on new vascular strategies for neurodegenerative disorders and Alzheimer's disease (AD). This proposal is focused on small resistance arteries that critically regulate cerebral blood flow (CBF) from the surface of the brain into the brain parenchyma. These arteries are often the site of amyloid deposition and pathology associated with cerebral amyloid angiopathy (CAA), one of the hallmarks of AD. Our preliminary data indicate that vascular smooth muscle cells (VSMCs) isolated from small arterial vessels from AD patients vs. age-matched controls have profound changes in gene expression profiles suggestive of a "mature differentiated" phenotype and "hypercontractility". In culture, we demonstrated significantly higher levels of contractile proteins (calponin, alpha-actin, SM22) associated with dysregulated expression of the transcription factors serum response factor (SRF) and myocardin, which play an important role in directing VSMC-differentiation program. Functional analysis in AD VSMC confirmed hypercontraction to potassium. Based on preliminary data, we hypothesize that CBF dysregulation in AD is due to an altered VSMC phenotype caused by dysregulated SRFImyocardin-directed differentiation program and associated loss of plasticity, impaired arteriogenesis, hypercontractility and loss of responsiveness to physiological modifiers. Phase I will validate SRF/myocardin as a therapeutic target in VSMCs in AD (aim 1) and determine the physiological responses of mouse blood vessels NSMC with altered levels of SRF/myocardin in an AD-like model of arterial dysfunction (aim 2). Phase II will use human and mouse models of AD-like VSMC dysfunction to screen reagents that could potentially control abnormal SRF/myocardin-directed VSMC differentiation program in AD, and will extend studies to animal models of AD/CAA and manipulated SRF. The Novelty of this proposal is focus on SRF/myocardin in VSMC as a major pathogenic factor for arterial disorder in AD and a major therapeutic target. Potential products to be ultimately developed are new drugs or genetic vectors that would affect SRF/myocardin function in small arteries in AD with a goal to improve CBF regulations by correcting plasticity, arteriogenesis and hypercontractility of VSMC.